Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene

Am J Med Genet A. 2017 Jun;173(6):1631-1634. doi: 10.1002/ajmg.a.38126. Epub 2017 Apr 13.


Heterozygous truncating mutations in ADNP are associated with a syndromic form of intellectual disability known as Helsmoortel-van der Aa syndrome. Among 17 previously reported patients with Helsmoortel-van der Aa syndrome, one patient exhibited blepharophimosis. Whether blepharophimosis represents a phenotypic expression of the ADNP mutation spectrum or a chance association remains unclear. Herein, we report another patient with a de novo truncating mutation in ADNP who exhibited a combination of blepharophimosis and epicanthal folds. In our retrospective re-evaluation of six originally reported patients whose facial photographs were available, at least one patient indeed had blepharophimosis and epicanthal folds. Furthermore, all three patients with blepharophimosis and epicanthal folds, including the presently reported patient, had truncating mutations at the same specific portion of the protein, that is the bipartite nuclear localization signal. We suggest that this specific class of ADNP mutation is likely associated with a blepharophimosis syndrome phenotype. From a clinical standpoint, a differential diagnosis of patients with blepharophimosis should include ADNP mutations in addition to blepharophimosis ptosis epicanthus inversus syndrome, especially when intellectual disability is present.

Keywords: ADNP; Helsmoortel-van der Aa syndrome; bipartite nuclear localization signal; blepharophimosis; blepharophimosis, ptosis, and epicanthus inversus syndrome; nonsense mediated mRNA decay.

Publication types

  • Case Reports

MeSH terms

  • Blepharophimosis / diagnostic imaging
  • Blepharophimosis / genetics*
  • Blepharophimosis / physiopathology
  • Child, Preschool
  • Face / physiopathology*
  • Heterozygote
  • Homeodomain Proteins / genetics*
  • Humans
  • Male
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Phenotype
  • Skin Abnormalities / diagnostic imaging
  • Skin Abnormalities / genetics*
  • Skin Abnormalities / physiopathology
  • Urogenital Abnormalities / diagnostic imaging
  • Urogenital Abnormalities / genetics*
  • Urogenital Abnormalities / physiopathology


  • ADNP protein, human
  • Homeodomain Proteins
  • Nerve Tissue Proteins

Supplementary concepts

  • Blepharophimosis, Ptosis, and Epicanthus Inversus